The present invention comprises a new class of compounds useful in treating diseases, such as diseases, conditions or disorders mediated by integrin receptors, such as vitronectin and fibronectin receptors. In particular, the compounds of the invention and pharmaceutical compositions thereof are useful for the prophylaxis and treatment of diseases, conditions or disorders involving atherosclerosis, restenosis, inflammation, cancer, osteoporosis and the like. This invention also relates to intermediates and processes useful in the preparation of such compounds.
Integrins are heteromeric cell surface receptors many of which have extracellular domains that bind to an Arg-Gly-Asp tripeptide (RDG) found in extracellular (plasma and matrix) proteins, such as fibronectin, vitronectin, fibrinogen and osteopontin. The fibrinogen receptor, gpIIb/IIIa integrin, is a platelet surface receptor that is thought to mediate platelet aggregation and the formation of hemostatic clot at bleeding wound sites (Blood. 71:831, 1988).
Vitronectin receptors, αvβ3 and αvβ5 integrin, are expressed by a number of cells, such as endothelial, smooth muscle, osteoclast, bone resorbing, tumor and epithelial cells. Integrin αvβ3 has been reported to be involved in bone resorption (Endocrinology 137:2347-54, 1996; J. Endocrinol. 154(Suppl.):S47-S56, 1997), in cell attachment, spreading and migration (Int. J. Biochem. Cell Biol. 31:539-544, 1999; Carreitas et al., Int. J. Cancer 80:285-294, 1999), in signal transduction, cell to cell interactions and is upregulated in response to vascular damage (Int. J. Biochem. Cell Biol. 29:721-725, 1997), in tumor cell invasion, angiogenesis, wound healing, phagocytosis of apototic cells and inflammation (J. Cell Biol. 144:767-775, 1999; Drug News Perspect. 10:456-461, 1997; Am. J. Pathol. 148:1407-1421, 1996), in tumor growth and hypercalcemia of malignancy (Cancer Res. 58:1930-1935, 1998), in tumorigenicity of human melanoma cells (Natali et al., Cancer Res. 57:1554-60, 1997), in melanoma metastasis (Cancer Metastasis Rev. 14:241-245, 1995; Cancer Metastasis Rev. 10:3-10, 1991), in the chondrocyte synthesis of matrix metalloproteinases (such as stromelysin, collagenase and gelatinase) which are involved in diseases such as rheumatoid arthritis and osteoarthritis (Arthritis Rheum. 38:1304-1314, 1995), in the progression of the renal injury in Fabry disease (Clin. Chim. Acta 279:55-68, 1999), and in viral infections (J. Virol. 72:3587-3594, 1998; Virology 203:357-65, 1994). Keenan et al. (J. Med. Chem. 40:2289-92, 1997) disclose examples of αvβ3 inhibitors which are selective for αvβ3 over platelet fibrinogen receptor (αIIbβ3).
Integrin αvβ5 (Smith et al., J. Biol. Chem. 265:11008-13, 1990) is thought to be involved in endocytosis and degredation of vitronectin (J. Biol. Chem. 268:11492-5, 1993), cellular locomotion of human keratinocytes (J. Biol. Chem. 269:26926-32, 1994), tumor cell metastasis (J. Clin. Invest. 99:1390-1398, 1997), differentiation of neuroblastoma metastasis (Am. J. Pathol. 150:1631-1646, 1997), and viral infections (Nat. Med. (N.Y.) 5:78-82, 1999; J. Cell Biol. 127:257-64, 1994).
Integrin αvβ6 is an RGD, tenascin and fibronectin binding protein (J. Biol. Chem. 267:5790-6, 1992) which is expressed by a number of cells, such as carcinoma and epithelial cells, and is thought to be involved in carcinoma cell proliferation (J. Cell Biol. 127:547-56, 1994), in wound healing and cell attachment (J. Invest. Dermatol. 106:42-8, 1996), in epithelial inflammation, such as asthma (J. Cell Biol. 133:921-928, 1996), in inducing gelatinase B secretion, activation of the protein kinase-C pathway, tumor cell spreading and proliferation in colon cancer cells (Biochem. Biophys. Res. Commun. 249:287-291, 1998; Int. J. Cancer 81:90-97, 1999), in regulation of pulmonary inflammation and fibrosis and binding and activating transforming growth factor β1 (Munger et al., Cell (Cambridge, Mass) 96:319-328, 1999), and in viral infections (Virology 239:71-77, 1997).
Antagonists of vitronectin receptors αvβ3, αvβ5 and/or αvβ6 have been reported to be useful in the treatment and prevention of atherosclerosis, restenosis, inflammation, wound healing, cancer (e.g., tumor regression by inducing apoptosis), metastasis, bone resorption related diseases (e.g., osteoporosis), diabetic retinopathy, macular degeneration, angiogenesis and viral disease.
Integrins have been associated with angiogenesis. Inhibitors of α5β1 integrin binding to its ligand in tissues have been reported to be useful in the treatment of angiogenesis (WO 99/58139).
WO 99/30709 and WO 99/30713 disclose compounds of the general formula W—X—Y—Z—CR5R6—CR7R8—CO2R9, wherein W, X, Y, Z, R5, R61 R7, R8 and R9 are as defined therein, as antagonists of integrin receptors αvβ3, αvβ5 and/or αvβ6.
WO 99/31099 discloses compounds, such as substituted 2-oxo-imidazolidin-1-yl-alkylcarboxylic acid and substituted 2-thiooxo-imidazolidin-1-yl-alkylcarboxylic acid compounds, as antagonists of integrin receptors αvβ3, αvβ5 and/or αvβ6.
WO 98/18461 discloses compounds of the general formula X—Y—Z-Ring-A—B, wherein X, Y, Z, Ring, A and B are as defined therein, as antagonists of integrin receptors αvβ3 and/or αvβ5.
U.S. Pat. No. 5,952,341 discloses compounds of the general formula X—Y—Z—C(O)—CH2—C(O)—NH—CR6R7—CR8R9—CO2R10, wherein X, Y, Z, R6, R7, R8, R9 and R10 are as defined therein, as antagonists of integrin receptors αvβ3 and/or αvβ5.
WO 97/08145 discloses compounds of the general formula wherein n, p, t, A, R, R1, R11, V, Y, Y3, Z, Z1 and Z3 are as defined therein, as integrin receptor inhibitors, in particular vitronectin (αvβ3) receptor inhibitors.
U.S. Pat. No. 5,843,906 discloses compounds of the general formula wherein t, A, B, R, R1, Y3, Z1, Z2, Z3, Z4 and Z5 are as defined therein, as integrin receptor inhibitors, in particular vitronectin (αvβ3) receptor inhibitors.
WO 97/36862 discloses compounds of the general formula wherein t, A, B, R, R1, Y, Y3, Z1, Z2, Z3, Z4 and Z5 are as defined therein, as integrin receptor inhibitors, in particular vitronectin (αvβ3) receptor inhibitors.
WO 99/33798 discloses compounds of the general formula wherein n, p, q, X, Y, R1, R2, R3, R4, Ra, Rb, Rc, Rd, Re, Rf and Rg are as defined therein, as vitronectin (αvβ3) receptor inhibitors.
WO 99/37621 discloses compounds of the general formula wherein R1, R2, R4, R5 and R6 are as defined therein, as inhibitors of bone resorption, cell adhesion and other diseases and disorders.
WO 99/32457 discloses compounds of the general formula wherein m, n, A, R1, R2, R4, R5 and R6 are as defined therein, as inhibitors of bone resorption, cell adhesion and other diseases and disorders.
U.S. Pat. No. 5,952,306 discloses compounds of the general formula X—(CH2)m—Y—(CH2)n—C(O)—N(R3)—CH2—C(O)—NH—CHR4—CHR5—CO2R61 wherein m, n, X, Y, R3, R4, R5 and R6 are as defined therein, as antagonists of GPIIbIIIa fibrinogen receptor.
U.S. Pat. No. 5,849,736 discloses compounds of the general formula wherein b, U, V, W, X, Y, R1, R14 and R15 are as defined therein, as antagonists of GPIIbIIIa fibrinogen receptor.
All of the above references cited herein are incorporated herein by reference in their entirety.